The present invention relates to a method for regulating the growth processes in a myriad of cells, tissues, organ systems and unicellular and multicellular organisms. More specifically, in accordance with the present invention, the fundamental growth processes in a multitude of biological systems can be modulated by the administration of the opioid antagonists naloxone, naltrexone, their analogs, metabolites, and/or derivatives.
In the past, naloxone and naltrexone have been employed predominantly for the treatment of narcotic addiction. Specifically, these compounds reverse the narcotic effects of exogenous opiates and opiate-like substances such as heroin and morphine, acting antagonistically thereto on a biochemical level.
Naloxone, the first of these compounds to be synthesized in 1960, was shortly thereafter discovered to have "pure" antagonist character, i.e., exhibiting virtually no agonist activity. Thus, naloxone became the preferred regime for the treatment of acute narcoticism.
However, since naloxone exhibited a relatively short duration in the body, it became clear that a longer acting agent having similarly "pure" antagonist character would be even more advantageous. Naltrexone was thus developed in 1965 in order to fulfill this requirement and was found to have greater potency and longer action than its N-allyl cogener, naloxone.
Since the discovery, during the early nineteen-seventies, of endogenous opioid substances, i.e., a group of pentapeptides produced by the cells of the brain and pituitary gland, and with the discovery of specific endogenous opioid receptor sites, there has been considerable interest in uncovering the possible roles of these endogenous compounds and their receptors in a variety of physiological and pharmacological processes. Many studies relating to these naturally occurring opioids and opioid-like substances such as leucine enkephalin, methionine enkephalin, dynorphin and beta-endorphin, collectively referred to as endorphins, have used antagonism by naloxone and/or naltrexone as a criterion for implicating the endogenous opioids in certain biological processes. Although it had been assumed that neither antagonist has pharmacological action other than that related to blockade of the opiate receptor, recent studies have indicated that these compounds may have some independent biological activity.
Furthermore, the discovery of the opioid receptor has also been the focus of extensive biochemical investigation into the mechanisms of tolerance and dependence. For example, it is reasonably well established that both exogenous and endogenous opioids and opioid-like substances modulate the pain threshold through stereospecific binding at the site of the opioid receptor. It has been determined that the administration of a concomitant amount of the compounds naloxone or naltrexone act competitively at the level of the receptor site to elicit an effect antagonistic to the narcotic, i.e., acting to blockade the receptor site and thus prohibiting the interaction between the opioid and the receptor site. The analgesic effect of the opioid is thereby prohibited or eliminated.
Recent studies have also determined that the exogenous opioids, specifically heroin, have some effect on tumor growth. In particular, heroin has been found to retard tumor growth and prolong survival time in mice with murine neuroblastoma, a well-characterized tumor that resembles human neuroblastoma. Moreover, it was found that this action could be blocked by the concomitant administration of the narcotic antagonist naloxone.
Although the opioids, their interrelationship with the respective narcotic antagonists and the stereochemical interaction which takes place at the site of the opioid receptors have all been the focal point of intensive investigative research, a litany of inconclusive results and seemingly contradictory observations have left much of this biochemical and physiological phenomenon substantially enigmatic. For example, fairly recent research has shown that, at certain levels, the administration of naloxone blocks the tumor growth-inhibitory effects of heroin. However, naloxone used alone, also demonstrates growth inhibitory action on tumorogenesis.
Therefore, in-view of this unreconciled data, an accurate receptor model of opioid action has not been designed heretofore, and more significantly, the role of the endogenous opioid system as a fundamental factor in controlling the growth processes of most biological systems has gone unrecognized.
The present invention, however, provides a consistent model for opioid receptor action which has been surprisingly discovered to involve the control of certain fundamental aspects of endogenous growth modulation in a myriad of living organisms.